We have continued studies of the effects of neonatal excitotoxic ventral hippocampal (VH) damage on dopamine- (DA) and glutamate-related neurotransmission. We report that VH lesioned rats have an abnormal response to various stressful stimuli. We have found that mild chronic stress differentially affects DA release and binding of certain ligands to dopamine receptors in control and VH lesioned animals. Stress results in reduced 3-methoxytyramine (3-MT) accumulation in prefrontal cortex, striatum and nucleus accumbens and increased striatal D4 antagonist, striatal emonopride (D2/D3/D4) and prefrontal cortical raclopride (D2/D3) binding in VH lesioned rats, but not in controls. VH lesion changes also serum corticosterone and 3-MT accumulation responses to acute footshock stress. Furthermore, VH lesioned rats are hyperresponsive to glutamatergic stimulation (MK-801, 0.2 mg/kg). Locomotor activity is profoundly increased in MK-801-treated lesioned rats over controls. In contrast to the lesion produced in the 7-day old (PD7) rats, lesion of the ventral hippocampus induced on PD14 results in prepubertal (PD35) emergence of long lasting amphetamine-induced hyperactivity. These results indicate that ventral hippocampal damage changes DA and glutamatergic responsiveness to pharmacological and stressful manipulations, and that the profile of changes are dependent on the age at which this damage is induced. We have also studied the effects of VH lesions on intracellular signal transduction mechanisms. We found that the VH lesion reduces expression of amphetamine-induced c-fos mRNA in cortical (medial prefrontal, piriform, and cingulate cortices) and subcortical (septum, striatum) regions. Changes are time-dependent and strain-specific. We also showed that mild chronic increases c-fos mRNA expression in the medial prefrontal cortex of control and VH lesioned rats. However, there is no differential effect of mild stress on serum corticosterone or c-fos expression in lesioned animals versus controls. In order to evaluate the effects of this neonatal lesion on antipsychotic drug-induced c-fos expression, we have performed in situ hybridization studies in acutely and chronically clozapine and haloperidol treated rats. We found that VH lesion alters the pattern of c-fos mRNA expression after clozapine and haloperidol treatment. The response to haloperidol is attenuated in lesioned rats. We have also studied the expression of a gene encoding limbic associated membrane protein (LAMP). VH lesion induced on postnatal day 7 (PD7) in adult (PD56) rats does not affect expression of LAMP mRNA in cortical regions, septum or nucleus accumbens. Our results indicate that developmental hippocampal damage alters intracellular signal transduction mechanisms in response to a pharmacological challenge, but it does not change the expression of LAMP in adulthood.